The present invention relates to novel quinolonecarboxylic acid derivatives or salts thereof, particularly to quinolonecarboxylic acid derivatives or salts thereof exhibiting potent antibacterial activity against gram-positive bacteria, in particular Propionibacterium acnes.
4-Oxoquinoline-1,4-dihydro-3-carboxylic acid derivatives are known to have antibacterial activity. For example, 4-oxoquinoline-1,4-dihydro-3-carboxylic acid compounds having pyridine connected to the 7-position thereof through a carbon-to-carbon bond are described in Published Examined Japanese Patent Application (Kokoku) No. Sho-55-50591, Published Unexamined Japanese Patent Application No. Hei-1-100166, etc.
Furthermore, 4-oxoquinoline-1,4-dihydro-3-carboxylic compounds having a cyclopropyl group at the 1-position thereof include many known compounds including ciprofloxacin.
Moreover concerning 4-oxoqinoline-1,4-dihydro-3-carobxylic acid derivatives, i.e., so-called topical quinolone for skin, only nadifloxacin is used clinically.
Nadifloxacin and the compounds described in the above publications have insufficient activity against purulent disease-causing gram-positive bacteria such as staphylococci, in particular Propionibacterium acnes. Therefore, development of synthetic antibacterial agents having potent and broad antibacterial spectra against these bacteria is being desired.
On the other hand, the safety of quinolone antimicrobial agents, for example, phototoxicity and mutagenicity is being discussed [Journal of Antimicrobial Chemotherapy, 33, 685-706 (1994), Henigensei Shiken (Mutagenicity Tests), 2(3), 154-161 (1993)].
Accordingly, development of quinolone-based synthetic antibacterial agents having not only potent antibacterial activity and broad antibacterial spectrum but also increased safety is being desired.
Under the circumstances, the present inventors have made intensive research and as a result they have found that quinolonecarboxylic acid derivatives or salts thereof represented by general formula [1], which have a cycloalkyl group at the 1-position, a pyridine group connected through a carbon-to-carbon bond to the 7-position and an alkyl or alkoxy group at the 8-position of 4-oxoquinoline-3-carboxylic acid, have excellent antibacterial activity against various gram-positive bacteria such as staphylococci and gram-negative bacteria such as Escherichia coli, particularly excellent antibacterial activity against Propionibacterium acnes and have high safety. The present invention has been achieved based on this discovery.
That is, the present invention provides novel quinolonecarboxylic acid derivatives or salts thereof represented by the following general formula 
(wherein R1 represents a hydrogen atom or a carboxyl-protective group; R2 represents an optionally substituted cycloalkyl group; R3 represents a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkoxy or alkylthio group, an optionally protected hydroxyl or amino group, or a nitro group; R4 represents an optionally substituted alkyl or alkoxy group; and Z represents a pyridin-4-yl or pyridin-3-yl group which may be substituted with at least one group selected from a halogen atom and an optionally substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio or amino group and an optionally protected hydroxyl or amino group).
Hereinafter, the compounds of the present invention will be described in detail.
Unless otherwise indicated specifically herein, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the alkyl group means a straight chain or branched chain C1-6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or pentyl; the alkenyl group means a straight chain or branched chain C2-6 alkenyl group, such as vinyl or allyl; the cycloalkyl group means a C3-6 cycloalkyl group, such as cyclopropyl, cyclopentyl or cyclohexyl; the alkylene group means a C1-6 alkylene group, such as methylene, ethylene or propylene; the alkoxy group means a straight chain or branched chain C1-6 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or pentyloxy; the alkylthio group means a straight chain or branched chain C1-6 alkylthio group, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio or pentylthio; the alkylamino group means an amino group substituted with one or more straight chain or branched chain C1-6 alkyl groups, such as methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino or dipentylamino; the aryl group means phenyl, naphthyl or the like; the heterocyclic group means a 4-, 5-or 6-membered ring or condensed ring thereof including at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom as hetero atom or atoms which constitutes or constitute the ring, for example, oxetanyl, thietanyl, azetidinyl, furyl, pyrrolyl, thienyl, oxazolyl, isooxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, benzofuranyl, benzothiazolyl, pyridyl, quinolyl, pyrimidinyl or morpholinyl group.
The cycloalkyl group in R2; the alkyl group, alkoxy group or alkylthio group in R3, the alkyl group or alkoxy group in R4; the alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio or amino group, which is a substituent group in pyridyl group in Z may be substituted with at least one group selected from a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally protected alkylamino group, an alkyl group, an alkoxy group, an aryl group, a cycloalkyl group and an alkenyl group and an alkyl group substituted with a halogen atom.
The carboxyl-protective group may include all the groups that can be usually used as a protective group for a carboxyl group, for example, alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, 1,1-dimethylpropyl, n-butyl and tert-butyl; aryl groups such as phenyl and naphthyl; aralkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis(p-methoxyphenyl)methyl; acylalkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; halogenoalkyl groups such as 2,2,2-trichloroethyl; alkylsilylalkyl groups such as 2-(trimethylsilyl)ethyl; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; nitrogen-containing heterocyclic alkyl groups such as phthalimidomethyl and succinimidomethyl; cycloalkyl groups such as cyclohexyl; alkoxyalkyl groups such as methoxymethyl, methoxyethoxymethyl and 2-(trimethylsilyl)ethoxymethyl; aralkoxyalkyl group such as benzyloxymethyl; alkylthioalkyl groups such as methylthiomethyl and 2-methylthioethyl; arylthioalkyl groups such as phenylthiomethyl; alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl and allyl; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl, and the like.
The protective groups for the amino group and alkyl amino group may include all the groups that can be usually used as protective groups for amino groups, for example, acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylcarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl and 8-quinolyloxycarbonyl; aralkyl groups such as benzyl, diphenylmethyl and trityl; arylthio groups such as 2-nitrophenylthio and 2,4-dinitrophenylthio; alkyl- or arylsulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; dialkylaminoalkylidene groups such as N,N-dimethylaminomethylene; aralkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene and 2-hydroxy-1-naphthylmethylene; nitrogen-containing heterocyclic aralkylidene groups such as 3-hydroxy-4-pyridylmethylene; cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3-dimethyl-5-oxycyclohexylidene; diaryl-or diaralkylphosphoryl groups such as diphenylphosphoryl and dibenzylphosphoryl; oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3-dioxol-4-ylmethyl; and substituted silyl groups such as trimethylsilyl, and the like.
The protective group for the hydroxyl group includes all the groups that can be usually used as a protective group for a hydroxyl group, for example, acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tertbutoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl and 2-trimethylsilylethyl; alkenyl groups such as allyl; aralkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl; alkoxyalkyl groups such as methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl) ethoxymethyl and 1-ethoxy-ethyl; alkyl-and arylsulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl, and the like.
The salts of the compounds of general formula [1] include usually known salts of basic groups such as amino groups, or salts of acidic groups such as hydroxyl or carboxyl groups.
The salts of basic groups may include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and acids with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid, and the like.
The salts of acidic groups may include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procain, dibenzylamine, N-benzyl-xcex2-phenethylamine, 1-ephenamine and N,Nxe2x80x2-dibenzylethylenediamine, and the like.
Among the above salts, preferred salts of the compounds of general formula [1] include pharmacologically acceptable salts.
Typical compounds of the present invention include, for example, the following compounds.
Abbreviations have the following meanings. Me: methyl, Et: ethyl, diMe: dimethyl, triMe: trimethyl, Cbz: benzyloxycarbonyl, cyclopropyl: cyclopropyl, pyridyl: pyridyl, oxide: oxide, diNH2: diamino.
Groups in the brackets in Z stand for substituent groups for a pyridyl group.
In the present invention, those compounds in which R2 is an optionally substituted cyclopropyl group; R3 is a hydrogen atom, an optionally substituted alkyl group or an optionally protected amino group; R4 is an optionally substituted alkyl or alkoxy group; Z is a pyridin-4-yl or pyridin-3-yl group substituted with an optionally substituted alkyl, alkoxy or amino group are preferred.
Furthermore, those compounds in which R2 is a cyclopropyl group; R3 is a hydrogen atom, an alkyl group or an amino group; R4 is an alkyl or alkoxy group; Z is a pyridin-3-yl group substituted with an optionally substituted alkyl, alkoxy or amino group are preferred.
Moreover, those compounds in which R2 is a cyclpropyl group; R3 is a hydrogen atom; R4 is a methyl or methoxy group; Z is a pyridin-3-yl group substituted with at least one group selected from a methyl group, a hydroxymethyl group, an amino group, a methylamino group or a dimethylamino group are preferred.
Where the compounds of general formula [1] or salts thereof have isomers (for example, optical isomers, geometrical isomers and tautomers), the present invention includes such isomers and also include solvates, hydrates and various forms of crystals.
Next, production methods of the compounds of the present invention will be described.
The compounds of the present invention can be synthesized, for example, by the following production methods. 
(In the above formulae, R1, R2, R3, R4 and Z have the same meanings as defined above; R5 and R6, which may be the same or different, represent a hydrogen atom, an alkyl group, or R5 and P6 together form a ring containing a boron atom; R7 represents an alkyl group; R8 represents an alkyl group; Y represents a halogen atom or a trialkylsilyloxy group; X represents a leaving group; Alk represents an alkyl group; X1 represents a halogen atom; R1a represents the same carboxyl-protective group as R1.)
The leaving group includes a chlorine atom, a bromine atom, an iodine atom, a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group and a p-fluorophenylsulfonyloxy group, etc.
The trialkylsilyloxy group includes tri-C1-5-alkylsilyloxy groups such as trimethylsilyloxy and triethylsilyloxy.
The ring containing a boron atom formed by R5 and R6 together includes 5- to 8-membered rings and condensed rings thereof, containing at least one hereto atom selected from an oxygen atom and a nitrogen atom as hetero atom or atoms constituting the ring, for example, 1,3,2-dioxaborolane, 1,3,2-dioxaborinane, 4H-dihydro-1,3,5,2-dioxaazaborinane, 1,3,5,2-trioxaborinane, 1,3,6,2-trioxaborocane and 1,3,6,2-dioxaazaborocane, etc.
The compounds of general formulae [1a] and [1b] may be in the form of salts. The salts may include the same salts as described on the compounds of general formula [1]. [Production Method 1] (1-a) The compounds of general formula [1] can be obtained by subjecting the compound of general formula [2a] and the compound of general formula [3a] to coupling reaction, or by subjecting the compound of general formula [2b] and the compound of general formula [4] to coupling reaction, in the presence or absence of silver oxide using a palladium catalyst.
The solvent used in the reaction is not particularly limited as far as it does not adversely affect the reaction. It includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; nitriles such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide, and the like. These may be used in admixture.
The palladium catalyst used in the reaction includes, for example, metallic palladium such as palladium-activated carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; and organic palladium complexes such as tetrakis(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium (II) chloride, bis(tricyclohexylphosphine)palladium (II) chloride and 1,1xe2x80x2-bis(diphenylphosphino)ferrocene palladium (II) chloride, and the like.
The use amount of palladium catalyst may be 0.00001 fold by mole or more, preferably 0.001 to 0.05 fold by mole, based on the compound of general formula [2a] or [2b].
When silver oxide is used in the reaction, the use amount of it may be equimolar or more, preferably 1 to 10 fold by mole, based on the compound of general formula [2a] or [2b].
The use amount of the organic tin of general formula [3a] may be equimolar or more, preferably 1.0 to 2.0 fold by mole, based on the compound of general formula [2a].
The use amount of the compound of general formula [4] may be equimolar or more, preferably 1.0 to 5.0 fold by mole, based on the compound of general formula [2b].
The coupling reaction may be practiced usually in an inert gas (for example, argon, nitrogen) atmosphere at 50 to 170xc2x0 C. for 1 minute to 24 hours. (1-b) As an alternative method, the compounds of general formula [1] can be obtained by subjecting the compound of general formula [2a] and the compound of general formula [3b] to coupling reaction in the presence or absence of a base using a palladium catalyst or a nickel catalyst.
The solvent used in the reaction is not limited particularly as far as it does not adversely affect the reaction. It includes, for example, water; alcohols such as methanol, ethanol and propanol; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; ethers such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as ethyl acetate and butyl acetate; ketones such as acetone and methyl ethyl ketone; nitrites such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide, and the like. These may be used in admixture.
In the reaction, the optionally used base includes, for example, sodium hydrogen carbonate, sodium carbonate, potassiumcarbonate, tripotassiumphosphate, cesiumcarbonate, cesium fluoride, potassium fluoride, sodium fluoride and triethylamine. The use amount of the base may be equimolar or more, preferably 2 to 5 fold by mole, based on the compound of general formula [2a].
The palladium catalyst used in the reaction may be the same catalyst as described in (1-a) above.
The nickel catalyst used in the reaction includes, for example, organic nickel complexes such as bis(diphenylphosphino)ethane nickel (II) chloride, bis(diphenylphosphino)propane nickel (II) chloride, bis(diphenylphosphino)butane nickel (II) chloride, bis(triphenylphosphine) nickel (II) chloride and 1,1xe2x80x2-bis(diphenylphosphino)ferrocene nickel (II) chloride.
The use amount of the compound of general formula [3b] may be equimolar or more, preferably 1.0 to 1.5 folds by mole, base on the compound of general formula [2a].
The use amount of the palladium catalyst or nickel catalyst may be 0.00001 fold by mole or more, preferably 0.001 to 0.05 fold by mole, based on the compound of general formula [2a].
The coupling reaction may be practiced usually in an inert gas (for example, argon, nitrogen) atmosphere at 50 to 170xc2x0 C. for 1 minute to 24 hours. [Production Method 2] (2-a) The compound of general formula [7] can be obtained by reacting the compound of general formula [5] with an ortho ester such as methyl orthoformate or ethyl orthoformate in acetic anhydride and then with the compound of general formula [6]. The compound of general formula [5] can be producedby the method described in J. Med. Chem., Vol. 336, p.1580-1596, 1993, or a method similar thereto.
The solvent used in the reactions is not limited particularly as far as it does not adversely affect the reaction. It includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; alcohols such as methanol, ethanol and propanol; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide, and the like. These solvents may be used in admixture.
In the reaction, the use amount of ortho ester may be equimolar or more, preferably 1 to 10 fold by mole, based on the compound of general formula [5].
The reaction may be practiced usually at 0 to 150xc2x0 C., preferably 50 to 150xc2x0 C., for 20 minutes to 50 hours.
In the subsequent reaction, the use amount of the compound of general formula [6] may be equimolar amount or more based on the compound of general formula [5], and the reaction may be practiced usually at 0 to 100xc2x0 C., preferably 10 to 60xc2x0 C., for 20 minutes to 30 hours. (2-b) As an alternative method, the compound of general formula [7] can be obtained by reacting the compound of general formula [5] with an acetal such as N,N-dimethylformamide dimethyl acetal or N,N-dimethylformamide diethyl acetal in the presence or absence of acid anhydride such as acetic anhydride and then with the compound of general formula [6].
The solvent used in these reactions is not particularly limited as far as it does not adversely affect the reactions. Specifically, it includes the same solvents as described in (2-a) above.
The use amount of acetal may be equimolar or more, preferably 1 to 5 fold by mole, based on the compound of general formula [5].
The use amount of acid anhydride may be equimolar or more, preferably 1 to 10 fold by mole, based on the compound of general formula [5].
The reaction may be practiced usually at 0 to 100xc2x0 C., preferably 20 to 85xc2x0 C., for 20 minutes to 50 hours.
In the subsequent reaction, the use amount of the compound of general formula [6] may be equimolar or more based on the compound of general formula [5] and the reaction may be practiced usually at 0 to 100xc2x0 C., preferably 10 to 60xc2x0 C., for 20 minutes to 30 hours. (2-c) The compounds of general formula [1a] can be obtained by subjecting the compounds of general formula [7] to cyclization reaction in the presence or absence of a fluoride salt or a base.
The solvent used in the reactions is not limited particularly as far as it does not adversely affect the reaction. It includes, for example, N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; ethers such as dioxane, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; and sulfoxides such as dimethyl sulfoxide, and the like. These solvents may be used in admixture.
The fluoride salt optionally used in the reaction includes, for example, sodium fluoride and potassium fluoride, and the like. The optionally used base includes, for example, sodium hydrogen carbonate, potassium carbonate, potassium tert-butoxide and sodium hydride, and the like.
The use amounts of fluoride salt and base each may be equimolar or more, preferably 1.0 to 3.0 fold by moles, based on the compound of general formula [7].
The reaction may be practiced usually at 0 to 180xc2x0 C. for 5 minutes to 30 hours. [Production Method 3] (3-a) The compounds of general formula [10] can be obtained by reacting the compound of general formula [8] with the compound of general formula [9] in which Y represents a halogen atom in the presence of a base or by reacting the compound of general formula (8) with the compound of general formula (9) in which Y represents a trialkylsilyloxy group in the presence of an acid.
The solvent used in the reactions is not particularly limited as far as it does not adversely affect the reactions. When Y is a halogen atom, the solvent includes, for example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; and aliphatic hydrocarbons such as pentane and hexane.
When Y is a trialkylsilyloxy group, the solvent includes, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-hexanol and cyclopropanol.
The base used in the reaction includes, for example, trialkylamines such as triethylamine.
The acid used in the reaction includes, for example, organic acids such as formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, toluylic acid, phthalic acid, methanesulfonic acid, benzenesulfonic acid and toluenensulfonic acid; and inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid.
The use amount of base may be equimolar or more, preferably 1 to 5 fold by mole, based on the compound of general formula [8].
The use amount of acid may be 0.005 to 50 fold by mole or more, preferably 0.1 to 20 fold by mole, based on the compound of general formula [8].
The use amount of the compound of general formula [9] may be 1.0 to 2.0 folds by mole, preferably 1.0 to 1.3 folds by mole, based on the compound of general formula [8].
The reactions may be practiced usually in an inert gas (for example, argon, nitrogen) atmosphere at xe2x88x9220 to 100xc2x0 C., preferably 20 to 90xc2x0 C., for 0.5 to 24 hours.
The compounds of general formula [10] can be used in the subsequent reaction without isolation.
The compounds of general formula [9] can be produced by the methods described in Organic Synthesis, Vol. 63, p. 147, 1985, J. Chem. Soc., Chem. Commun., p. 897, 1987, etc. or methods similar thereto. (3-b) The compounds of general formula [11] can be obtained by subjecting the compounds of general formula [10] to reduction reaction.
The solvent used in the reaction is not limited particularly as far as it does not adversely affect the reaction. It includes, for example, ethers such as tetrahydrofuran, diethyl ether, dioxane, 1,2-diemthoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and tetraethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol and isopropanol, and the like. These solvents may be used in admixture.
The reducing agent used in the reaction includes, for example, sodium borohydride in the presence of boron trifluoride, such as boron trifluoride ether complex or boron trifluoride tetrahydrofuran complex; sodium borohydride in the presence of a metal halide compound; sodium borohydride; aluminohydride complexes such as lithium aluminohydride, and the like.
The metal halide compound used in the reduction reaction includes aluminum chloride, iron (III) chloride, zinc chloride, cobalt (II) chloride, platinum (II) chloride, ruthenium (II) chloride, rhodium (II) chloride, palladium (II) chloride, zirconium (IV) chloride, calcium chloride and lithium chloride, and the like.
As the reduction reaction, catalytic reduction using metallic palladium such as palladium-activated carbon may be performed.
The use amount of the reducing agent may vary depending on the type of the reducing agent. For example, in the case of sodium borohydride, it is equimolar or more, preferably 1.0 to 2.5 fold by mole based on the compound of general formula [10].
The use amounts of boron trifluoride ether complex and boron trifluoride tetrahydrofuran complex are equimolar or more, preferably 1.3 to 3.3 fold by mole based on the compound of general formula [10].
The reaction may be practiced usually at xe2x88x9220 to 100xc2x0 C., preferably at xe2x88x925 to 80xc2x0 C., for 2 to 10 hours. (3-c) The compounds of general formula [13] can be obtained by reacting the compounds of general formula [11] with the compounds of general formula [12] in the presence or absence of solvents.
The solvent which is optionally used in the reaction is not particularly limited as far as it does not adversely affect the reaction. It includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide, and the like. These may be used in admixture.
The use amount of the compound of general formula [12] may be equimolar or more, preferably 1 to 10 fold by mole, based on the compound of general formula [11].
The reaction may be practiced preferably at 50 to 150xc2x0 C. for 20 minutes to 50 hours.
The compounds of general formula [13] or salts thereof can be used in the subsequent reaction without isolation. (3-d) The compounds of general formula [1b] or salts thereof can be obtained by subjecting the compounds of general formula [13] to cyclization reaction in the presence or absence of solvents.
The cyclization reaction may be performed by heating in the presence or absence of cyclizing agents.
The cyclizing agent used in the reaction includes, for example, polyphosphoric acid, polyphosphoric acid esters, phosphorus pentoxide, concentrated sulfuric acid and the like cyclizing agents.
When the heating is performed in the absence of cyclizing agents, the optionally used solvent is not particularly limited as far as it does not adversely affect the reaction. It includes, for example, high boiling inert solvents such as biphenyl, diphenyl ether, o-dichlorobenzene and dibutyl phthalate. These may be used in admixture. The reaction may be practiced usually at 50 to 260xc2x0 C. for 1 minute to 50 hours, preferably at 100 to 260xc2x0 C. for 10 minutes to 3 hours.
The solvent which is optionally used upon heating in the presence of cyclizing agents is not particularly limited as far as it does not adversely affect the reaction. It includes, for example, benzene, dioxane and dimethylformamide when polyphosphoric acid, a polyphosphoric acid ester, phosphorus pentoxide or the like is used as a cyclizing agent. When concentrated sulfuric acid is used as a cyclizing agent, the solvent includes acetic anhydride and acetic acid. The solvents may be used in admixture.
The use amount of cyclizing agent may be equimolar amount or more, preferably 1 to 10 folds by mole, based on the compound of general formula [13].
The reaction may be practiced usually at 50 to 260xc2x0 C. for 1 minute to 50 hours, preferably at 50 to 140xc2x0 C. for 10 minutes to 3 hours.
The compounds of general formulae [1], [1a] and [1b] thus obtained can be subjected to a reaction known per se, such as oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or suitable combinations thereof, so that they can be derived to other compounds of general formula [1].
The compounds of general formula [1] or salts thereof can be isolated and purified by conventional methods such as extraction, crystallization, and/or column chromatography.
Next, production methods of the compounds of general formulae [2a], [2b], [5] and [8], starting compounds for the production of the compounds of the present invention, will be explained.
The compounds of general formulae [2a] and [2b] can be produced by the methods described in International Publication No. WO96/05192 and Japanese Patent Application No. 8-47936 or methods similar thereto. Alternatively, they can be obtained by the following methods. 
(In the formulae, R1, R1a, R2, R3, R4 R5, R6, R7, R8, Alk, X, Y and Z have the same meanings as defined above.)
The compounds of general formula [16] can be produced from the compounds of general formula [14] according to the methods described in J. Am. Chem. Soc., Vol. 118, p. 7215-7216, 1996, J. Am. Chem. Soc., Vol. 118, p. 7217-7218, 1996, Tetrahedron Letters, Vol. 37, p. 4463-4466, 1996, Tetrahedron Letters, Vol. 38, p. 2073-2074, 1997, Tetrahedron Letters, Vol. 36, p. 3609-3612, 1995, J. Org. Chem., Vol. 61, p. 1133-1135, 1996 or methods similar thereto. More specifically, they can be produced, for example, by the following method.
The compounds of general formula [16] can be obtained by subjecting the compounds of general formula [14] and the compounds of general formula [15] to coupling reaction in the presence of a palladium catalyst, a base and a ligand.
The solvent which is optionally used in the reaction is not particularly limited as far as it does not adversely affect the reaction. It includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; nitriles such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide, and the like. These may be used in admixture.
The palladium catalyst used in the reaction includes, for example, metallic palladium such as palladium-activated carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; and organic palladium complexes such as tetrakis(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium (II) chloride, bis(tricyclohexylphosphine)palladium (II) chloride and 1,1xe2x80x2-bis(diphenylphosphino)ferrocene palladium (II) chloride, and the like.
The use amount of palladium catalyst may be 0.00001 fold by mole or more, preferably 0.001 to 0.05 fold by mole, based on the compound of general formula [14].
The base used in the reaction includes, for example, potassium tert-butoxide, sodium tert-butoxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, triethylamine, and the like.
The use amount of the base may be equimolar or more, preferably 2 to 5 fold by mole, based on the compound of general formula [14].
The ligand used in the reaction includes, for example, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, tri-(orthotolyl)phosphine, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(diphenylphosphino)propane, 1,2-bis(diphenylphosphino)benzene, 1,2-bis(diphenylphosphino)ethylene and 1,1xe2x80x2-bis(diphenylphosphino)ferrocene, and the like.
The use amount of the ligand in the reaction may be 0.00001 fold by mole or more, preferably 0.001 to 0.05 fold by mole, based on the compound of general formula [14].
The use amount of the compound of general formula [15] may be equimolar or more, preferably 1.0 to 1.5 fold by mole, based on the compound of the formula [14].
The coupling reaction may be practiced usually in an inert gas (for example, argon, nitrogen) atmosphere at 50 to 170xc2x0 C. for 1 minute to 24 hours.
As an alternative method, the compounds of general formula [16] can be produced by subjecting the compounds of general formula [20] to reduction reaction.
The solvent used in the reaction is not limited particularly as far as it does not adversely affect the reaction. It includes, for example, alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; aromatic hydrocarbons such as benzene, toluene and xylene; and water, and the like. These may be used in admixture.
The reducing agent used in the reaction includes, for example, alkali metals such as lithium, sodium and potassium; alkaline earth metals such as magnesium and calcium; zinc; metal salts such as aluminum, chromium, titanium, iron, cobalt, platinum, rhodium, palladium, ruthenium, samarium and selenium hydrosulfite sodium salts; metal hydrides such as diisobutylaluminum hydride, trialkylaluminum hydride, tin hydride compounds and hydrosilane; borohydride complexes such as sodium borohydride, lithium borohydride, potassium borohydride and calcium borohydride; aluminohydride complexes such as lithium aluminohydride; and boranes and alkylboranes, and the like.
The use amount of the reducing agent used in the reaction may vary depending on the type of the reducing agent. For example, in the case of borohydride complexes, it is 0.25 fold by mole or more, preferably 1.0 to 2.0 folds by mole, based on the compound of general formula [20].
The reduction reaction may be practiced usually at xe2x88x9220 to 120xc2x0 C., preferably 0 to 80xc2x0 C., for 10 minutes to 24 hours.
The compounds of general formula [20] can be obtained by subjecting the compounds of general formula [18] to ordinary reduction reaction to convert them to the compounds of general formula [19] and then reacting the compounds of general formula [19] with the compounds of general formula [9] in the presence of acids.
The solvent used in the reaction includes alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-hexanol, cyclopentanol and cyclohexanol. These may be used in admixture.
The acid which is used in the reaction includes, for example, organic acids such as aliphatic carboxylic acids, e.g., formic acid, acetic acid, propionic acid and butyric acid; aromatic carboxylic acids, e.g., benzoic acid, toluylic acid and phthalic acid; aliphatic sulfonic acids, e.g., methanesulfonic acid; aromatic sulfonic acids, e.g., benzenesulfonic acid and toluenesulfonic acid and inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid.
The use amount of acid may be 0.005 fold by mole or more, preferably 0.1 to 20 fold by mole, based on the compound of general formula [19].
The use amount of the compound of general formula [9] may be equimolar or more, preferably 1.0 to 1.3 fold by mole, based on the compound of general formula [19].
The reaction may be practiced usually at 0 to 120xc2x0 C., preferably 20 to 100xc2x0 C., for 10 minutes to 24 hours.
The compounds of general formula [17] can be obtained by reacting the compounds of general formula [16] with the compounds of general formula [12], for example, alkoxymethylenemalonic acid dialkyl esters such as diethyl ethoxymethylenemalonate in the presence or absence of solvents.
The solvent optionally used in the reaction is not particularly limited as far as it does not adversely affect the reaction. It includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide, and the like. These solvents may be used in admixture.
The use amount of alkoxymethylenemalonic acid dialkyl esters maybe equimolar or more, preferably 1 to 10 fold by mole, based on the compound of general formula [16].
The reaction may be practiced preferably at 50 to 150xc2x0 C. for 20 minutes to 50 hours.
The compounds of general formula [17] may be used in the subsequent reaction without isolation. (A-a) The compounds of general formula [2a] can be obtained by subjecting the compounds of general formula [17] to heating reaction in the presence or absence of solvents.
The solvent which is optionally used in the reaction is not particularly limited as far as it does not adversely affect the reaction. It includes, for example, high boiling inert solvents such as biphenyl, diphenyl ether, orthodichlorobenzene and dibutyl phthalate. These may be used in admixture.
The reaction may be practiced usually at 50 to 260xc2x0 C. for 1 minute to 50 hours, preferably at 100 to 260xc2x0 C. for 10 minutes to 3 hours. (A-b) The compounds of general formula [2a] can be obtained by subjecting the compounds of general formula [17] to heating reaction in the presence of a cyclizing agent and in the presence or absence of solvents.
The cyclizing agent used in the reaction includes, for example, polyphosphoric acid, polyphosphoric acid esters, phosphorus pentoxide, concentrated sulfuric acid and the like cyclizing agents.
The solvent optionally used in the reaction is not particularly limited as far as it does not adversely affect the reaction. In addition to the solvents exemplified in (A-a) above, it includes, for example, benzene, dioxane and dimethylformamide when polyphosphoric acid, a polyphosphoric acid ester, phosphorus pentoxide or the like is used as a cyclizing agent. When concentrated sulfuric acid is used as a cyclizing agent, the solvent includes acetic anhydride and acetic acid. The solvents to be used may be used in admixture.
The use amount of cyclizing agent may be equimolar or more, preferably 1 to 10 fold by mole, based on the compound of general formula [17].
The reaction may be practiced usually at 50 to 260xc2x0 C. for 1 minute to 50 hours, preferably at 50 to 140xc2x0 C. for 10 minutes to 3 hours.
In the reaction, hydrolysis reaction of ester groups proceeds simultaneously, so that among the compounds of general formula [2a], those compounds in which R1 is a hydrogen atom can also be obtained directly.
The compounds of general formula [2b] can be obtained by subjecting the compounds of general formula [2a] and hexaalkyldistannan to coupling reaction using a palladium catalyst.
The hexaalkyldistannan includes hexabutyldistannan.
The solvent used in the reaction is not limited particularly as far as it does not adversely affect the reaction. It includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; nitrites such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide, and the like. These solvents may be used in admixture.
The palladium catalyst used in the reaction includes, for example, metallic palladium such as palladium-activated carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; and organic palladium complexes such as tetrakis(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium (II) chloride, bis(tricyclohexylphosphine)palladium (II) chloride and 1,1xe2x80x2-bis(diphenyl-phosphino)ferrocene palladium (II) chloride, and the like.
The use amount of palladium catalyst may be 0.00001 fold by mole or more, preferably 0.001 to 0.05 fold by mole, based on the compound of general formula [2a].
The use amount of hexaalkyldistannan may be equimolar or more, preferably 1.0 to 3.0 fold by mole, based on the compound of general formula [2a].
The coupling reaction maybe practiced usually in an inert gas (for example, argon, nitrogen) atmosphere at 50 to 170xc2x0 C. for 1 minute to 24 hours. (A-c) The compounds of general formula [21] can be obtained by subjecting the compounds of general formula [18] and the compound of general formula [3b] in the presence or absence of bases using a palladium catalyst.
The solvent used in the reaction is not particularly limited as far as it does not adversely affect the reaction. It includes, for example, water; alcohols such as methanol, ethanol and propanol; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; ethers such as dioxane, tetrahydrofuran, anisole, 1,2-dimethoxyethane, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as ethyl acetate and butyl acetate; ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide, and the like. These may be used in admixture.
The base optionally used in the reaction includes, for example, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, tripotassiumphosphate, cesium carbonate, cesium fluoride, potassium fluoride, sodium fluoride and triethylamine.
The palladium catalyst used in the reaction includes, for example, metallic palladium such as palladium-activated carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; and organic palladium complexes such as tetrakis(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium (II) chloride, bis(tricyclohexylphosphine)palladium (II) chloride and 1,1xe2x80x2-bis(diphenylphosphino)ferrocene palladium (II) chloride, and the like.
The use amount of the base used in the reaction may be equimolar or more, preferably 2 to 5 fold by mole, based on the compound of general formula [18].
The use amount of the palladium catalyst may be 0.00001 fold by mole or more, preferably 0.001 to 0.005 fold by mole, based on the compound of general formula [18].
The use amount of the compound of general formula [3b] may be equimolar or more, preferably 1.0 to 1.5 fold by mole, based on the compound of general formula [18].
The coupling reaction may be practiced usually in an inert gas (for example, argon, nitrogen) atmosphere at 50 to 170xc2x0 C. for 1 minute to 24 hours. (A-d) The compounds of general formula [8] can be produced by subjecting the compounds of general formula [21] to reduction reaction.
The solvent used in the reaction is not particularly limited as far as it does not adversely affect the reaction. It includes, for example, alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diethylene glycol diethyl; nitrites such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; and water, and the like. These may be used in admixture.
The reducing agent used in the reaction includes, for example, metals such as zinc, aluminum, iron and tin and salts thereof; borohydride complexes such as sodium borohydride, lithium borohydride, potassium borohydride and calcium borohydride, and the like. When iron is used as a reducing agent, ammonium chloride may be used as a reaction promoter.
As the reduction reaction, catalytic reduction using metallic palladium such as palladium-activated carbon may be carried out.
The use amount of the reducing agent used in the reaction may vary depending on the type of the reducing agent. It is equimolar or more, preferably 1 to 5 fold by mole, based on the compound of general formula [21].
The use amount of the reaction promoter may be equimolar, preferably 0.1 to 3 fold by mole, based on the compound of general formula [21].
The reaction may be practiced usually at xe2x88x9220 to 150xc2x0 C., preferably 0 to 100xc2x0 C., for 10 minutes to 24 hours. (A-e) The compounds of general formula [8] can be obtained by subjecting the compound of general formula [19] and the compound of general formula [3b] to coupling reaction in the presence or absence of a base using a palladium catalyst or a nickel catalyst.
The solvent used in the reaction is not limited particularly as far as it does not adversely affect the reaction. It includes, for example, water; alcohols such as methanol, ethanol and propanol; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; ethers such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as ethyl acetate and butyl acetate; ketones such as acetone and methyl ethyl ketone; nitrites such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide, and the like. These may be used in admixture.
The base optionally used in the reaction includes, for example, sodium hydrogen carbonate, sodium carbonate, potassiumcarbonate, tripotassiumphosphate, cesiumcarbonate, cesium fluoride, potassium fluoride, sodium fluoride and triethylamine.
The palladium catalyst used in the reaction includes, for example, organic palladium salts such as palladium acetate; and organic palladium complexes such as tetrakis(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium (II) chloride, bis(tricyclohexylphosphine)palladium (II) chloride and 1,1xe2x80x2-bis (diphenylphosphino)ferrocene palladium (II) chloride, and the like.
The nickel catalyst used in the reaction includes, for example, organic nickel complexes such as bis(diphenylphosphino)ethane nickel (II) chloride, bis(diphenylphosphino)propane nickel (II) chloride, bis(diphenylphosphino)butane nickel (II) chloride, bis(triphenylphosphine) nickel (II) chloride and 1,1xe2x80x2-bis(diphenylphosphino)ferrocene nickel (II) chloride.
The use amount of the base may be equimolar or more, preferably 2 to 5 fold by mole, based on the compound of general formula [19].
The use amount of the palladium catalyst or nickel catalyst may be 0.00001 fold by mole or more, preferably 0.001 to 0.05 fold by mole, based on the compound of general formula [19].
The use amount of the compound of general formula [3b] may be equimolar or more, preferably 1.0 to 1.5 fold by mole, based on the compound of general formula [19].
The coupling reaction may be practiced usually in an inert gas (for example, argon, nitrogen) atmosphere at 50 to 170xc2x0 C. for 1 minute to 24 hours.
The compounds of general formula [3b] can be produced by subjecting halogeno heterocyclic rings to boration reaction.
The reaction may be practiced by the methods described in Jikken Kagaku Koza, 4th edition, Vol. 24, p. 61-91, 1992 and J. Org. Chem., Vol. 58, p. 201-2208, 1993 and methods similar thereto.
The compounds of general formulae [3a] and [4] can be produced by the methods described in Dai Yuki Kagaku 16 [III], 1 (1969), Shin Jikken Kagaku Koza, 14 [IV], p. 2056 (1978), etc. and methods similar thereto.
In the production methods described above, the compounds of general formulae [1a], [2a], [2b], [3a], [3b], [4], [5], [7], [8], [10], [11], [13], [14], [15], [16], [17], [18], [19], [20] and [21] may be used in the form of their salts. The salts include the same salts as those explained as the salts of the compounds of general formula [1].
In the production methods described above, the compounds of general formulae [2a], [2b], [3a], [3b], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20] and [21] maybe isomers (for example, optical isomers, geometrical isomers and tautomers) if such exist. Also, solvates, hydrates and various forms of crystals thereof may also be used.
Among the compounds of the formulae formulae [1a], [1b], [2a], [2b], [3a], [3b], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20] and [21], those compounds having an amino group, a hydroxyl group or a carboxyl group may be protected in advance with an ordinary protective group, which is then eliminated after the reaction by a method known per se.
When the compounds of the present invention are used as medicines, they may be mixed with pharmaceutical ingredient conventionally used in formulating pharmaceutical preparations, such as excipients, carriers and diluents. They may be administered by oral or parenteral administration in the form of tablets, capsules, powder, syrup, granules, pills, suspensions, emulsions, liquids, powdery preparations, suppositories, eye drops, nasal drops, ear drops, dressings, ointments, or injections in accordance with the conventional method. Preferably, they may be prepared as parenteral drugs, particularly drugs for application to mucosa or topical preparations. The administration method, dose and number of times of administration can be selected appropriately depending on the age, weight and symptom of patients. Usually, the compounds of the present invention may be administered to adults at a dose of 0.1 to 100 mg/kg at a time or in several times in portions by oral or parenteral administration (for example, injection, drip infusion and administration to rectal portion. Preferably, they may be administered at the same dose as above by parenteral administration, for example, application to mucosa or topical administration to the skin.
Next, the pharmacological activities of typical compounds of the present invention will be explained.
a: 1-Cyclopropyl-7-(2,6-dimethyl-4-pyridyl)-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
b: 1-Cyclopropyl-7-(2-hydroxymethyl-6-methyl-4-pyridyl)-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
c: 1-Cyclopropyl-7-(6-methyl-3-pyridyl)-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
d: 1-Cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
e: 7-(6-Amino-5-methyl-3-pyridyl)-1-cyclopropyl-8-(difluoromethoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
f: 7-(6-Amino-5-methyl-3-pyridyl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
g: 7-(6-Amino-5-methyl-3-pyridyl)-1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
h: 7-(6-Amino-3-pyridyl)-1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
i: 1-Cyclopropyl-7-(2,6-dimethyl-4-pyridyl)-5,8-dimethyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
j: 5-Amino-1-cyclopropyl-7-(5,6-dimethyl-3-pyridyl)-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
k: (Control): (xc2x1)-9-Fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1-1H,5H-benzo[i,j ]quinolizine-2-carboxylic acid [general name: nadifloxacin]
The drug sensitivity of Propionibacterium acnes (P. acnes JCM6425) was assayed according to the standard method of Japan Chemotherapy Society [CHEMOTHERAPY, Vol. 41, No. 2, p. 183-189 (1993)]. More particularly, the test bacteria cells on the modified GAM agar [GAM agar, modified xe2x80x9cNissuixe2x80x9d] (manufactured by Nissui Seiyaku) medium incubated at 35xc2x0 C. for 2 days were suspended in modified GAM bouillon (GAM broth, modified xe2x80x9cNissuixe2x80x9d) [manufactured by Nissui Seiyaku] to 1 McFarand and the cell suspension was diluted 5 fold with the same medium to obtain a cell suspension for inoculation. The cell suspension was inoculated in the wells of a micro plate, each dispensed with 100 xcexcl of modified GAM bouillon containing the drug in two-fold dilution series to a final cell density of 105 CFU/well, and incubated in an anaerobic incubator (Forma Scientific anaerobic system: model 1024) at 35xc2x0 C. for 2 days. MIC (xcexc/ml) was defined as the lowest concentration which inhibited visible growth of the cells. The results obtained are shown in Table 1.
According to the standard method of Japan Chemotherapy Society [CHEMOTHERAPY, Vol. 29, No. 1, p. 76-79 (1981)], Staphylococcus aureus (S. aureus F-1924) was cultivated in Mueller Hinton broth [manufactured by Difco] at 37xc2x0 C. for 20 hours and the cell density was adjusted to 106 cells/plate (108 cells/ml). A loopful of the bacterial suspension was inoculated on Mueller Hinton agar medium [manufactured by Difco] and incubated at 37xc2x0 C. for 20 hours. Whether or not the growth of cells occurred was observed and MIC (xcexcg/ml) was defined as the lowest concentration which inhibited visible growth of the cells. The results obtained are shown in Table 2.
According to the description in Dokusei Shiken Koza 12 (Chijinshokan, 1991), pages 147-153, micronucleus test was carried out using ddy male mice. As a result, the compounds (a), (c), (d) and (g) were negative when administered intraperitoneally at 500 mg/Kg.
Three ddy male mice were intraperitoneally administered with 500 mg/Kg of (a), (b), (d) or (g). In no case, the animals were dead.